Each year the European Society for Medical Oncology (ESMO) meeting gathers thousands of multidisciplinary oncology professionals to discuss the latest developments in cancer management. This year, to achieve its goal of bringing innovation to cancer patients, ESMO held a virtual ‘Science Weekend’ on 19-21 September with over 30,000 registered attendees and 2,137 presented abstracts; an ‘Educational Weekend’ will be held on 16-20 October, 2020. During the first Presidential Symposium, Toni Choueiri, MD (Dana Farber Cancer Institute, Boston, MA, USA) presented the eagerly awaited first results from the randomized, open-label phase III CheckMate 9ER trial that evaluated nivolumab in combination with cabozantinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC).

Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor (ICI), and the TKI cabozantinib, are each approved for the treatment of aRCC. Since the combination of these agents has shown promising antitumor activity in a phase I study of patients with advanced genitourinary cancers, the phase III CheckMate 9ER trial was designed to investigate the efficacy and safety of nivolumab plus cabozantinib in combination versus sunitinib in treatment-naive patients with clear cell aRCC. Patients (n= 651) were randomly assigned to receive either the combination of nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg daily) or sunitinib (50 mg daily, 4 weeks on, 2 weeks off) The primary endpoint of the trial was progression-free survival (PFS) per blinded independent central review (BIRC), and secondary endpoints were overall survival (OS), objective response rates (ORR), and safety. Exploratory endpoints included health-related quality of life (HRQoL) and efficacy in predefined subgroups. At a median follow-up of 18.1 months, the trial met all efficacy endpoints, demonstrating the superiority of first line nivolumab plus cabozantinib over sunitinib. Median PFS was 16.6 months with the combination versus 8.3 months with sunitinib (hazard ratio [HR] 0.51, P <0.0001). Similarly, patients receiving the combination had significantly longer OS than those receiving sunitinib (medians not reached, HR 0.6; P = 0.001). Furthermore, ORR was doubled in the combination arm (55.7% versus 27.1%) with higher complete responses (CR) with the combination (8% versus 4.6%). Median time to response was shorter (2.8 versus 4.2 months) and median duration of response was longer (20.2 versus 11.5 months) with the combination compared with sunitinib, respectively. In addition, nivolumab plus cabozantinib showed consistent efficacy benefits over sunitinib across all predefined subgroups, including International Metastatic RCC Database Consortium (IMDC) risk groups, PD-L1 expression and bone metastases. Treatment-related adverse events (TRAEs) were similar across both arms, with TRAEs of ≥ grade 3 occurring in 61% versus 51% of patients in the combination and sunitinib arms, respectively; a higher incidence of elevated transaminases was seen in the combination arm. TRAEs leading to discontinuation occurred more commonly in the combination arm (15.3% versus 8.8%); however, discontinuation of both agents was rare (3.1%). Immune-related AEs were mostly low grade; 19% of patients received corticosteroids to manage their irAEs.Of note, HRQoL was maintained over time with the combination treatment, and disease-related symptoms improved from baseline; conversely, patients in the sunitinib arm experienced a deterioration in quality of life and disease-related symptoms.

Based on these results that demonstrate superior efficacy with first-line nivolumab plus cabozantinib for patients with aRCC, along with the favorable quality of life data, Dr Chouieri concluded that the combination is a potential new first-line option for patients with aRCC. A discussant for the trial, Camillo Porta, MD (University of Bari, Bari, Italy) highlighted the challenges of selecting optimal immunotherapy-based regimens for patients with aRCC, given that nivolumab plus cabozantinib and other immunotherapy-based combinations, including nivolumab plus ipilimumab and pembrolizumab plus axitinib, all have impressive efficacy but with differences in long-term clinical benefit and toxicity. He noted that the choice of therapy is currently driven only by the biological aggressiveness of the tumor, and heemphasized the need for further investigation in clinical trials to clarify the optimal use of each regimen.

Reference

Choueiri TK, et al. Annals of Oncol. 2020;31 (suppl_4; abstract 6960_PR)